Pancreatic cancer is often a fatal disease with 5-year survival rates of only 1-4%. Early detection can substantially reduce the mortality rate. Mutations of the KRAS oncogene (mainly in codon 12) are present in <90%-95% of cases of pancreatic cancer. KRAS mutations are not specific to pancreatic cancer, but early detection of these mutations in high-risk individuals, combined with the diagnostic follow-up, can save lives. Stool is a very attractive source of cancer-derived DNA that can be used for early screening. However, the hostile environment of the gastrointestinal tract composed of bile salts, DNases, and proteases reduces the chances that pancreatic cancer cells and cancer DNA will survive during the passage. This could be one of the reasons for low sensitivity of detection of pancreatic cancer-related mutations in stool. In order to improve the sensitivity of pancreatic cancer screening in stool samples, we propose to design and test ingestible polymer-coated nano- and microparticles that will be capable of binding and protecting DNA, including pancreatic cancer DNA, until it is excreted in stool. Our specific aims are: (1) Using pancreatic tumor DNA that has KRAS G12D mutation, optimize capture and protection efficiency by the particles in vitro in the presence of bile and pancreatic juice components; (2a) By feeding cancer DNA and the particles to normal mice, test the recovery of KRAS mutations in stool; (2b) Using triple knockout (KRAS-cre-p53) pancreatic cancer model (KPC), test the increase in sensitivity of detection of KRAS mutation in stool. This project will have a high impact on the diagnosis and monitoring of pancreatic cancers. Specifically, the proposed method for non-invasive sampling of cancer DNA can improve feasibility of early screening of pancreatic cancer in high-risk populations, and can be developed into a cost effective early screening and monitoring tool. PUBLIC HEALTH RELEVANCE: Early detection of pancreatic cancer can substantially reduce the mortality rate. We propose to design and test a novel approach to improve the sensitivity of detection of pancreatic cancer mutations in stool. This project will have a high impact on the diagnosis and monitoring of pancreatic cancers, especially for screening in high-risk populations.